Clinical features and CACNA1A gene mutation in a family with episodic ataxia type 2 / 中南大学学报(医学版)

Episodic ataxia (EA) is a group of disorders characterized by recurrent spells of vertigo, truncal ataxia, and dysarthria. Episodic ataxia type 2 (EA2), the most common subtype of EA, is an autosomal dominant disease caused by mutation of the CACNA1A gene. EA2 has been rarely reported in the Chinese population. Here we present an EA2 family admitted to Xiangya Hospital in October 2018. The proband was a 22-year-old male who complained of recurrent spells of vertigo, slurred speech, and incoordination for 4 years. Brain magnetic resonance imaging (MRI) showed cerebellar atrophy. He had neuropsychological development disorder in childhood, and cognitive assessment in adulthood showed cognitive impairment. The proband's mother and grandmother had a similar history. Peripheral blood samples from the proband and family members were collected, and genomic DNA was isolated. Whole exome sequencing of the proband detected a heterozygous frameshift mutation c.2042_2043del (p.Q681Rfs*100) of CACNA1A gene. This mutation was verified in the proband and 2 family members using Sanger sequencing. One family member carrying this mutation was free of symptoms and signs, suggesting an incomplete penetrance of the mutation. We reported a variant c.2042_2043del of CACNA1A gene as the pathogenic mutation in a Chinese EA2 family for the first time. This case enriched the clinical spectrum of CACNA1A related EA2, and contributed to the understanding of clinical and genetic characteristics of EA2 to reduce misdiagnosis.

Clinical and imaging features of idiopathic intracranial hypertension / 中南大学学报(医学版)

OBJECTIVES@#Idiopathic intracranial hypertension (IIH) is a syndrome that excludes secondary causes such as intracranial space-occupying lesion, hydrocephalus, cerebrovascular disease, and hypoxic ischemic encephalopathy. If not be treated promptly and effectively, IIH can cause severe, permanent vision disability and intractable, disabling headache. This study aims to explore the clinical and image features for IIH, to help clinicians to understand this disease, increase the diagnose rate, and improve the outcomes of patients.@*METHODS@#We retrospectively analyzed 15 cases of IIH that were admitted to Xiangya Hospital, Central South University, during January 2015 to September 2020. The diagnosis of IIH was based on the updated modified Dandy criteria. We analyzed clinical data of patients and did statistical analysis, including age, gender, height, weight, medical history, physical examination, auxiliary examination, treatment and outcome.@*RESULTS@#There were 10 females and 5 males. Female patients were 22 to 42 years old with median age of 39.5. Male patients were 27 to 52 years old with the median age of 44.0. The BMI was 24.14-34.17 (28.71±2.97) kg/m@*CONCLUSIONS@#IIH primarily affects women of childbearing age who are overweight. The major hazard of IIH is the severe and permanent visual loss. Typical image signs have high specificity in IIH diagnosis. Prompt diagnosis and effective treatment are significantly important to improve the outcomes of patients.

The latest research progress: Exosomal microRNAs as biomarkers for diagnostic and therapeutic application in Alzheimer’s disease / 中华老年医学杂志

Exosomes are spherical microvesicles(30-100 nm)secreted by a variety of cells and contain a variety of proteins, lipids, mRNAs, and microRNAs.These molecules into exosomes can be transferred to adjacent cells and distant tissues or cells by exosomes to develop full effects.Exosomes-released microRNAs are involved in the pathogenesis of Alzheimer's disease(AD)by regulating the abnormal expression of amyloid β-protein(Aβ)and p-Tau protein, initiating the inflammatory response by interacting with toll-like receptors.In addition, exosomal microRNAs can be used as a potential therapeutic target for AD.Exosomes as good carriers have great research values.This review summarized the literatures related to the role of exosomal microRNAs in the development of AD and the potential therapeutic effect on AD.A large amount of evidence indicates that expression disorder of exosomal microRNA plays an important role in the pathogenesis of AD and can be used as a new potential biomarker and therapeutic target for the diagnosis and treatment of AD.

Clinical and image features for 12 cases of cerebral autosomal dominant arteriopathy with the subcortical infarcts and leukoencephalopathy / 中南大学学报(医学版)

To analyze the clinical and image features for 12 patients of cerebral autosomal dominant arteriopathy with subcortical infarct and leucoencephalopathy (CADASIL).
 Methods: A total of 12 CADASIL patients were collected in Xiangya Hospital of Central South University from January 2013 to December 2018. The clinical manifestation, risk factors, MRI imaging data and NOTCH3 mutations were analyzed retrospectively.
 Results: The mean age of 12 patients was (47.25±9.49) years. The clinical manifestation was most common in cognitive impairment (75%) and stroke events (58.3%), and 2 cases showed cerebral hemorrhage. Migraine was only seen in 25% patients. All MRI showed white matter hyperintensity (WMH), lacune and enlarged perivascular space (PVS). WMH mainly occurred in the frontal parietal lobe (100%), temporal lobe (83.3%), external capsule (66.7%), occipital lobe (41.6%), callosum 41.6% and the temporal pole (33.3%), while lacune mainly appeared in frontal lobe (91.6%), parietal lobe(83.3%), temporal lobe(66.7%), basal ganglia (66.7%), brain stem (41.6%), occipital lobe (33.3%), cerebellum (8.3%). Enlarged PVS located in the basal ganglia (100%), partly under the cortex (45.4%). WMH of the patient with intracerebral hemorrhage was mild (Fezakas score 1-2), which was not found in external capsule. 16.7% of the patients had intracranial arterial stenosis. In 12 patients, 8 different Notch3 mutations were detected. The c1013G>c p.(Cys338Ser) located in exon 6, which was a new pathogenic mutation of CADASIL.
 Conclusion: The patients with cerebral hemorrhage have mild WMH and specific genotype, indicating that the clinical characteristics of CADASIL with cerebral hemorrhage may be related to image features and genotype.

Myopathy associated with anti-signal recognition peptide antibodies: Five case reports / 中南大学学报(医学版)

Five patients with myopathy associated with anti-signal recognition peptide antibodies, admitted to our hospital from December 2015 to June 2018, were chosen in our study, and their clinical and pathological manifestations and treatments were retrospectively analyzed. Five patients showed subacute or chronic onset and proximal limb muscle weakness. Serum creatine kinase level was significantly elevated. Immunoblotting assay confirmed the positive anti-signal recognition particle antibody. EMG prompted myogenic damage. Pathological features included muscle degeneration, necrosis with regeneration, visible atrophy and hypertrophic of muscle fiber, connective tissue hyperplasia and a small amount of inflammatory cell infiltration. Immunohistochemical staining showed necrotizing muscle fiber infiltrated with CD4-positive and CD8-positive lymphocytes and CD68-positive macrophages, and no CD20-positive lymphocytes and CD303-positive dendritic cells were observed. Two patients had expressed a bit of c5b-9 positive capillary. Anti-sarcoglycans staining, anti-dysferlin staining and dystrophin staining showed continuous strong positive expression. Follow-up study found that all patients were response to glucocorticoid, and a combination therapy of immunoglobulin and immunosuppression were necessary for some patients.

Etiologies and risk factors for young people with intracerebral hemorrhage / 中南大学学报(医学版)

To determine the etiologies and risk factors of intracerebral hemorrhage in young people.
 Methods: A total of 401 young patients with intracerebral hemorrhage were enrolled, and they were assigned into a 20-29 , a 30-39, and a 40-45 age group. The differences of various etiologies and risk factors among the three groups were analyzed.
 Results: There were 273 men and 128 women in the 401 young patients. The etiologies of 294 patients (73.32%) were identified while 107 patients (26.68%) were unknown. Among those with identified etiology, 226 patients (56.36%) suffered from hypertension, 41 patients (10.22%) congenital cerebrovascular malformation (including 25 patients with cerebral arteriovenous malformation, 8 intracranial cavernous hemangioma, and 8 intracranial aneurysm), and 27 other etiologies (including 9 patients with moyamoya disease, 6 cerebral venous sinus thrombosis, 4 drug abuse, 3 hemorrhagic brain tumor, 2 intracranial infection, 1 systemic lupus erythematosus, 1 drug-induced, and 1 eclampsia). Risk factors included hypertension (237 cases, 59.10%), smoking (123 cases, 30.67%), alcohol consumption (74 cases, 18.45%), and others (19 cases, 4.74%; including 8 cases of pregnancy or in the puerperium, 8 family history of intracerebral hemorrhage, and 3 taking anti-platelet aggregation/anticoagulation agents). The rate of hypertension induced hemorrhage significantly increased with age (P<0.01); the rate of vascular malformations in 20-29 age group was obviously higher than other groups (P<0.01); the rate of unknown cause in the 40-45 age group was significantly lower than other groups (P<0.01) and the rate of other etiologies showed no significant difference in the 3 groups. The rate of hypertension was significantly elevated with the age (P<0.01), while smoking, alcohol consumption, and other risk factors showed no significant difference in the 3 groups.
 Conclusion: The rate of intracerebral hemorrhage in young people increases with the increasing of age and hemorrhage affects men more than women; hypertension may be the main cause and congenital cerebrovascular malformation is the second cause, which may be more common in younger patients. Hypertension, smoking, and alcohol consumption may be the major controllable risk factors in intracerebral hemorrhage in young people.

Clinical characteristics of hemichorea associated with non-ketotic hyperglycemia in 3 patients: case report and literature review / 中南大学学报(医学版)

Objective:To investigate the pathophysiology,clinical manifestation and neuroimaging characteristics and therapeutic experiences for hemichore associated with non-ketotic hyperglycemia (HC-NH).Methods:Clinical data of three patients with HC-NH from Xiangya Hospital,Central South University were analyzed retrospectively,and the related literature was reviewed.Results:The core clinical features of HC-NH were characterized by acute/subacute onset of hemichorea with non-ketotic hyperglycemia in the elderly females.Radiologic findings associated with HC-NH were characterized by hyperattenuation on computed tomographic (CT) scans and hyperintensity on Tl-weighted magnetic resonance imaging (MRI) at unilateral basal ganglion region.Blood glucose control was the foundation of treatment.Dopamine receptor antagonists and benzodiazepine sedative were helpful in controlling hemichorea.Conclusion:Hemichorea-hemiballismus is a rare complication of nonketotic hyperglycaemia in elderly type 2 diabetes.It is associated with contralateral striatal radiological abnormality and typically T1 hyperintensity on MRI.The pathophysiology of HC-NH is not clear.The prognosis of HC-NH is favorable.Antidiabetic drugs combined with dopamine receptor antagonists can effectively relieve the hemichorea symptoms.

NOTCH3 gene mutations in two Chinese families featuring cerebral autosomal dominant arteriopathy with subcortical infarct and leucoencephalopathy / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To analyze potential mutations of the NOTCH3 gene in two Chinese families featuring cerebral autosomal dominant arteriopathy with subcortical infarct and leucoencephalopathy (CADASIL).</p><p><b>METHODS</b>The two probands and related family members and 100 healthy controls were recruited. Potential mutations of the NOTCH3 gene were screened by PCR and direct sequencing. PolyPhen-2 and SIFT software were used to predict the protein function.</p><p><b>RESULTS</b>The conditions of both probands were adult-onset, with main clinical features including recurrent transient ischemic attacks and/or strokes, cognitive impairment. MRI findings suggested multiple cerebral infarcts and severe leukoencephalopathy. A heterozygous mutation c.328C>T (p.Arg110Cys), which was located in exon 3 of the NOTCH3 gene and known as a causative mutation, was identified in proband 1. A novel heterozygous mutation c.1013 G>C (p.Cys338Ser) located in exon 6 of the NOTCH3 gene was identified in the proband 2, which was not reported previously. The same mutations were not detected among the 100 unrelated healthy controls. Function analysis suggested that heterozygous mutation c.1013G>C can severely affect the functions of NOTCH3 protein.</p><p><b>CONCLUSION</b>Two heterozygous missense mutations in the NOTCH3 gene have been identified in two families affected with CADASIL. The novel heterozygous Cys338Ser mutation in exon 6 of the NOTCH3 gene probably underlies the CADASIL.</p>

Mutations analysis of SPG11 gene in Chinese Han patients with hereditary spastic paraplegia / 中华神经科杂志

Objective To identify disease-causing mutations in a large panel of Chinese Han patients with hereditary spastic paraplegia(HSP).Methods The coding sequence of the SPG11 gene in the probands of 28 families with ARHSP and 14 sporadic HSP patients was analyzed,and the identified changes in the sequence were tested to exclude being a benign polymorphism by sequencing 200 chromosomes from normal controls.Results Identified 13 causative mutations in SPG11 gene in 7 ARHSP and 3 sporadic HSP The mutations were:c.5977C>T/p.Q1993X、c.4668T>A/p.Y1556X、c.6898_6899delCT/p.L2300AfsX23.38、c.3719_3720delTA/p.11240VfsX263、c.733_734delAT/p.M245VfsX246、c.7088_7089insATTA/p.Y2363X、c.2163_2164insT/p.1722Yfsx731、c.7101-7102insT/p.K2368X、c.6790_6791insC/p.12264PfsX2339、c.654_655delinsG/p.S218RfsX219、c.7151+4_7151+7delAGTA/p.K2384fsX2386、c.6355-21_6355-18delTCT、c.3004C>T/p.G1002X.Among them,12 were novel mutations.The rate of mutation in the SPG11 gene was 25.0%(7/28)in ARHSP,6/6 in ARHSP-TCC and 3/14 in sporadic cases.Conclusions In Chinese Han population,patients with ARHSP-TCC and sporadic HSP-TCC should be screened for SPG11.Sequencing of the SPG11 gene in these patients with is valuable for clinical diagnostic testing.